Autism is a common, complex disorder with high heritability and unknown genetic causes. One approach to discover genetic factors involved in autism is to investigate overlapping molecular pathways with related autism-spectrum disorders with known genetic causes. Rett syndrome (RTT), an X-linked dominant disorder caused by mutations in MECP2 (methyl CpG binding protein 2), and Angelman syndrome (AS), an imprinting disorder caused by maternal 15q11-13 deficiencies, share many features with autism. Maternal 15q11-13 duplications in autistic individuals and rare MECP2 mutations occurring in autism and AS point to genetic overlap between these disorders. Studies on human post-mortem brain samples demonstrated overlapping pathways in the molecular pathogenesis of these disorders. Specifically, GABRB3, a 15q11-13 gene encoding the beta 3 subunit of the receptor for the neurotransmitter GABA, has reduced protein expression in RTT, AS, and a subset of autism brain samples. Reduced GabrbS expression in the Mecp2- deficient mouse has lead to the hypothesis that MeCP2 regulates GABRBS expression in brain. The goal of this proposal is to further investigate 15q11-13 expression defects in autism samples and determine what role MeCP2 plays in regulating gene expression in this region. Semi-quantitative western blotting and quantitative RT-PCR will be used to further assess the expression levels of three 15q11-13 GABA-A receptor genes in post-mortem human brain samples from controls, autism, and RTT patients. Epigenetic abnormalities, including aberrant DMA methylation and imprinting, will be investigated in genomic brain DMA from samples with expression abnormalities using bisulfite sequencing and allelic expression analysis. Finally, the involvement of MeCP2 in 15q 11 -13 GABA-A receptor expression will be experimentally tested using a human neuroblastoma cell line. siRNA in combination with biochemical techniques, such as ChIP and chromosome conformation capture, will be used to test the hypothesis that MeCP2 directly binds to and is involved in regulating the 15q11-13 GABA-A receptor genes. [unreadable] [unreadable] Autism is a common and complex disorder with a strong genetic component. Although the genes that cause autism remain unclear, chromosome 15 contains a set of genes that are duplicated in some cases of autism. Previous studies suggest chromosome 15 genes may be involved in some autism cases without duplications, therefore the aims of this research proposal seek to identify the role that these genes play in causing autism. [unreadable] [unreadable] [unreadable]